tbuckley/cabot-search huggingface dataset:
Abstract 14559: Anti-Arrhythmic Effects of Exosomes Isolated From Cardiosphere-Derived Cells in Rats With Heart Failure and Preserved Ejection Fraction
Authors: Jae Hyung Cho, Alex Rajewski, Catherine Bresee, Myung Yoon Kim, Thassio Mesquita, Xaviar Jones, Isabelle Pellot, Weixin Liu, Lizbeth Sanchez, Asma Nawaz, Ahmed G Ibrahim, Russell Rogers, Eugenio Cingolani, Eduardo Marban
Journal: Circulation (2022)

Introduction: Cardiosphere-derived cells (CDCs) reverse electrical remodeling and reduce inducible ventricular arrhythmias in rats with heart failure and preserved ejection fraction (HFpEF). Exosomes isolated from CDCs (CDCexo) have anti-arrhythmic effects in various animal models but have not been tested in models of HFpEF. Hypothesis: CDCexo, when given intravenously, reverse electrical remodeling and reduce spontaneous ventricular arrhythmias in rats with HFpEF. Methods: Dahl salt-sensitive rats were fed high-salt diet (containing 8% NaCl) to induce HFpEF from 7 weeks of age. Ambulatory electrocardiogram (ECG) devices were implanted in the peritoneum at 13 weeks of age to monitor spontaneous ventricular arrhythmias. Exosomes were harvested from media conditioned by human CDCs after 48 hours of exposure to hypoxia. Echocardiogram-verified HFpEF rats (at 14 weeks of age) were injected via tail vein with human CDCexo (n=8) vs. vehicle (IMDM media, n=8) weekly for 4 weeks. ECG parameters and spontaneous development of ventricular arrhythmias were compared between the two groups. Results: QTc interval was reduced in CDCexo-injected HFpEF rats compared to vehicle-injected HFpEF rats (262±15 ms vs. 287±25 ms, p=0.0001). Two of the eight HFpEF rats injected with vehicle showed a maximal premature ventricular contraction (PVC) burden per minute of 50% while only one HFpEF rat injected with CDCexo manifested 25% maximal PVC burden per minute. Five of eight HFpEF rats injected with vehicle showed non-sustained ventricular tachycardia (VT) while only one HFpEF rat infused with CDCexo developed non-sustained VT. One rat in the vehicle group undergoing telemetry monitoring died suddenly and the cause of death was sustained VT degenerating into ventricular fibrillation (VF). The number of VT/VF episodes per rat (including non-sustained VT and sustained VT/VF) was reduced in the CDCexo group compared to the vehicle group (0.4 [0-3] vs. 13 [0-56] episodes per rat, p=0.0443). Conclusions: CDCexo recapitulated the beneficial effects of CDCs in HFpEF rats: reversing electrical remodeling and reducing ventricular arrhythmias. More importantly, an intravenous delivery route was effective for CDCexo to confer their salutary effects to rats with HFpEF.
Abstract 15260: Role Of Purinergic Dysfunction in Worsened Outcomes for Females Undergoing Cardiac Surgery
Authors: Eitizaz Mahmood, Adnan A Khan, Nada Qureshi, Ruma Bose, Feroze Mahmood, Marie-France Poulin, Kamal R Khabbaz, Frank Sellke, simon robson, Robina Matyal
Journal: Circulation (2022)

Objective: To determine whether purinergic signaling plays a role in the adverse outcome in females presenting for cardiac surgery Methods: Right atrial tissue was harvested from 80 patients undergoing CABG surgery before and after and cardiopulmonary bypass (CBP). Human tissue experimentation was complemented by experiments in mice subject to a high fat diet and ovariectomy. Western blot and immunohistochemistry was carried out to interrogate the molecular derangements. Results: Females (n=40) had increased diastolic dysfunction (56% vs. 31%, p = .034) and length of stay (7.9 vs. 5.4 days, p = .02). We found that CD39, responsible for the enzymatic lysis of inflammatory extracellular ATP, was significantly decreased in women after CBP. Moreover, female patients demonstrated increased expression of ADORA2B, which acts as a pro-fibrotic agent responsive to adenosine as well as increased CD73, which is responsible for the lysis of adenosine monophosphate into adenosine. Finally, females demonstrated decreased adenosine deaminase, which breaks adenosine into inosine. Female patients had increased fibrosis and decreased angiogenesis (Figure 1a). Mouse models showed a similar decrease in purinergic ectonucleotidase activity as a result of ovariectomy and estrogen loss when compared to controls (Figure 1b). Conclusions: Purinergic signaling may serve as a key upstream mechanism responsible for the molecular derangements which underlie poorer outcomes for women following CABG surgery.
Abstract 15607: Right Ventricular Diastolic Function: A Machine Learning-Based Echocardiographic Classification Scheme
Authors: Ella Shaviv, Zara Vajihi, Igal Sebag, Lawrence G Rudski, Christos Galatas, Victoria Hayman, Nancy Murray, Marie-Josée Blais, Jonathan Afilalo
Journal: Circulation (2022)

Background: Right ventricular (RV) diastolic dysfunction is associated with heart failure and adverse cardiac events. Echocardiography guidelines include a limited assessment of RV diastology based on a scheme borrowed from the left ventricle, which is suboptimal. Hypothesis: An RV-specific classification scheme could be developed using echocardiographic parameters and machine learning to better reflect right-sided physiology and diagnose diastolic dysfunction. Methods: A total of 540 consecutive outpatients undergoing clinically-indicated echocardiograms at the Jewish General Hospital between March and December 2019 were prospectively recruited. Measurements relevant to RV diastology were acquired in triplicate by trained cardiac sonographers and verified by level III echocardiography staff and fellows. A sequential approach of unsupervised and supervised machine learning was used to develop a de novo classification model for RV diastology. Results: First, to prevent the use of redundant echocardiographic parameters within any given model, a feature-level clustering algorithm classified the 35 candidate parameters into mutually exclusive groups (for example, a group containing various size parameters). Second, a patient-level clustering algorithm analyzed all possible combinations of parameters in order to classify patients into three groups: normal, intermediate, and abnormal diastolic function. Third, a decision tree algorithm analyzed the top performing combinations in order to rank the importance of the echocardiographic parameters in predicting the diastology groups. Finally, after selecting the most predictive parameters - Ep, Ep/Ap, and IVC sniff - the final decision tree algorithm was generated. The prevalence of heart failure increased stepwise from 14% in the normal group, to 19% in the intermediate group, and 32% in the abnormal group. Conclusions: Our echocardiographic classification scheme for RV diastology is uniquely tailored to right-sided physiology and identifies patients with increasing rates of heart failure. Further study is warranted to validate this scheme in an independent population and examine its prognostic value for adverse cardiac events.
Abstract 14973: Upregulated Sphingosine-1-Phosphate Receptor 3 Disrupts Endothelial Cell Barrier and Mitochondrial Network Dynamics
Authors: Jialin Wu, Ying Liang, Xutong Sun, Qing Lu, Kim Tieu, Stephen M Black, Ting Wang
Journal: Circulation (2022)

Introduction: Ventilator-Induced Lung Injury (VILI) exacerbates existing Acute Lung Injury (ALI) of ICU patients via mechanical ventilation. However, the cellular and molecular mechanism behind VILI is still poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive lipid which usually enhances vascular endothelial barrier via S1P receptor 1 (S1PR1) to protect against ALI. VILI associated mechanical stress reduces S1PR1 while increases S1P receptor 3 (S1PR3) expression. S1PR3 couples to Rho, a central regulator of cytoskeleton and mitochondrial network dynamics. Therefore, the upregulation of S1P-S1PR3 pathway is highly likely to be involved in the deterioration of endothelial barrier and mitochondrial function during VILI. Methods and Results: Cyclic stretch (18%) significantly increased S1PR3 levels (1.85±0.12 fold, n=3, p&lt;0.05) in human lung endothelial cells (EC). After S1PR3 overexpression (S1PR3 OE), EC basal resistance was reduced (62.8±4.3%, n=8, p&lt;0.05) in ECIS experiments. Moreover, S1P (100 nM) increased 37.2±4.1% resistance in control cells (n=5, p&lt;0.05), while decreased 32.0±3.2% resistance in S1PR3 OE cells (n=5, p&lt;0.05). In contrast to S1P-induced junctional distribution of VE-cadherin in control cells, S1P failed to cause any VE-cadherin junctional redistribution in S1PR3 OE cells as shown by Immunofluorescence (Fig. 1). We further confirmed that S1PR3 OE suppresses VE-cadherin expression in human ECs by western blot. In addition, in S1PR3 OE cells, S1P challenge induced an increased mitochondrial ROS release as shown by MitoSOX assay (6.87±1.10 fold, n=3, p&lt;0.05) and a mitochondrial fission phenotype that was not observed in control cells. Conclusions: VILI associated mechanical stress upregulates S1PR3, leading to the reprograming of endothelial cell cytoskeleton regulatory machinery and mitochondrial network dynamics. S1PR3 might be a promising target to ameliorate the damage caused by mechanical ventilation.
Abstract 14524: Low Testosterone Levels and Cardiovascular Disease: Insights From the Houston Methodist CVD Registry
Authors: Tamer Yahya, Shannon Lu, Rakesh Gullapelli, Shubham Lahan, Mohamad Taha, Omar M Makram, Fady Jaawan, BUDHADITYA BOSE, Nwabunie Nwana, Stephen Jones, Kershaw Patel, Ahmed Soliman, Miguel Cainzos Achirica, Logan C Hubbard, Nathan Starke, Khurram Nasir
Journal: Circulation (2022)

Introduction: Low testosterone (LowT) has been suggested to be associated with increased ASCVD risk and mortality, but results are conflicting across studies. We evaluated the independent relationship between low testosterone levels in adult males and ASCVD using data from an EHR-based database. Methods Cross-sectional study using the Houston Methodist CVD Learning Health System Registry, which includes data from 1.1 million patients aged ≥18 years (June 2016-April 2022). Analyses were restricted to men, and those on testosterone replacement therapy were excluded. We evaluated the associations between total testosterone levels (categorized as quartiles [Q], lowest Q as exposure of interest and highest Q as reference) and ASCVD (CAD, PAD, stroke), using logistic regression. Conditions and risk factors were identified using ICD 10-CM codes. Results: We evaluated 30,150 men ≥18 years (mean age 55.3 years, 12% NHB, 15% Hispanics) with testosterone level data. Men in testosterone Q1 (lowest levels: ≤285 ng/dl) had higher prevalence of almost all risk factors and composite ASCVD compared to Q4 (highest levels: ≥515 ng/dl) (Panel A). In unadjusted analyses, men in testosterone Q1 vs Q4 had higher odds of ASCVD (OR 1.54, 95% CI 1.41-1.68). In multivariable adjusted logistic regression, the increased odds persisted adjusting for age, sex, and race OR 1.33 (CI 1.21 - 1.46), while it was fully attenuated (OR 1.04 CI 0.94 - 1.14) after adjusting for risk factors (DM, HTN, dyslipidemia, obesity) (Panel B). The attenuation in association with prevalent ASCVD was highest adjusting for DM (67%) and HTN (58%) (Panel C). Similar results were noted when cutoff of &lt;200 ng/dl was used for LowT. Conclusions: ASCVD and CV risk factors are widely prevalent among men with LowT. The association between LowT and ASCVD might be related to CV risk factors, mainly hypertension and DM. Early identification and intensive CV risk factor management among men with LowT levels may help reduce their risk of ASCVD.
Abstract 14774: Association Between Cumulative Lipoprotein(a) Exposure and Adverse Cardiovascular Outcomes in Patients With Prediabetes or Diabetes: Insights From an Asian Cohort Following Percutaneous Coronary Intervention
Authors: Peizhi Wang, Jinqing Yuan
Journal: Circulation (2022)

Introduction: Lipoprotein(a) is a complex circulating lipoprotein and growing evidence has demonstrated its role as a risk factor for coronary artery diseases and as a promising therapeutic target. However, the impact of cumulative Lp(a) exposure on long-term cardiovascular prognosis remains indistinct. Hypothesis: The aim of this study is to determine the impact of cumulative Lp(a) exposure [CumLp(a)] on long-term cardiovascular prognosis in patients with CAD and different glycemic metabolism status. Methods: We consecutively enrolled 10,724 patients with CAD hospitalized for PCI from January to December in 2013. Cumulative Lp(a) exposure was calculated as the area under the Lp(a) versus age trajectory. According to the optimal cut-off value of CumLp(a) for the major adverse cardiac and cerebrovascular events risk prediction and different glycemic metabolism status, patients were categorized into six groups. Results: 9,329 patients were ultimately enrolled in the current study. 2,073 MACCEs were documented during a median of 5 years’ follow-up. CumLp(a) was a significantly independent prognostic factor in the total population, in the Pre-DM groups and in the DM groups (HR: 1.45, 95% CI 1.12-1.89, P = 0.006; HR: 1.08, 95% CI 1.01-1.16, P = 0.018; HR: 1.07 95% CI 1.00-1.13, P = 0.037; respectively). Moreover, compared to ones with CumLp(a)-L and non-DM, patients with CumLp(a)-H and DM, CumLp(a)-H and Pre-DM, and CumLp(a)-L and DM had increased risk of 5-year MACCEs (HR: 1.50, 95% CI 1.21-1.87, P &lt; 0.001; HR: 1.39 95% CI 1.11-1.73, P = 0.004; HR: 1.33, 95% CI 1.08-1.64, P = 0.008; respectively). Conclusions: In this real-world study, higher level of CumLp(a) combined with DM or Pre-DM was significantly related to worse 5-year cardiovascular outcomes among patients with CAD undergoing PCI, suggesting that evaluation of CumLp(a) and impaired glycemic metabolism status may help identify high-risk individuals who would benefit from further therapeutic interventions.
Abstract 15599: Sex-Based Differences in Coronary Artery Morphology, Disease Distribution, and Lesion Outcomes
Authors: Aditya Jain, Ozan Unlu, Paolo Di Achille, Eugene V Pomerantsev, Joseph M Garasic, Patrick T Ellinor, Anthony A Philippakis, AKL C FAHED
Journal: Circulation (2022)

Introduction: Despite the unique pathophysiology, clinical presentation, and disparities in care of women with coronary artery disease, sex-based differences in coronary morphology and their relation to disease remain poorly understood. Methods: We constructed a retrospective cohort of adult patients who underwent a coronary angiogram between 2000 and 2021 at Massachusetts General Hospital and compared dominance, branching, and coronary lesion location and severity at baseline between males and females. We mapped lesions over time and studied differences in risk of receiving a future intervention by sex of the patient and location of the lesion in the coronary tree. Results: 50,988 patients (age 65.7+12.8 years, 33.0% female) had a baseline coronary angiogram and 174,502 lesions were reported. Compared to males, females were less likely to have left or mixed dominance (15.7% vs. 17.4% p&lt;0.001) and trifurcation of the left main (LM) (5.9% vs. 11.1%, p&lt;0.001). Compared to males, females had more lesions reported in the left anterior descending (30.0% vs. 28.3%, p&lt;0.001) and right coronary artery (26.5% vs. 24.4% p&lt;0.001), and less lesions in branches - obtuse marginal, diagonal, posterior descending, and posterolateral (21.8% vs. 25.1%, p&lt;0.001). Obstructive disease - defined as ≥50% stenosis in the LM or ≥70% stenosis in any other vessel - was less common in females (48.8% vs. 69.1% , p&lt;0.001). 8,432 patients (age 65.8+11.0 years, 25.8% female) with 37,842 lesions were evaluated longitudinally over a median follow-up of 2.9 (IQR 0.9-6.7) years, excluding follow-up of ≤2 months. The adjusted hazard ratio for need for a future intervention was 1.16 (95% CI 1.08-1.25) in females as compared to males, but this varied significantly by location in the coronary tree and sex (Figure). Conclusions: Significant sex-based differences in coronary artery morphology, location, and disease distribution exist. Their interplay may inform future need for intervention.
Abstract 171: Correlation Between The Neurological Pupil Index And Blood Brain Barrier Permeability In Out Of Hospital Cardiac Arrest Patients Treated With Target Temperature Management
Authors: Yeonho You, Changshin Kang, Hong Joon J Ahn, Jung Soo Park, Won-joon Jeong, Jinhong Min, Yong N In
Journal: Circulation (2022)

BBB disruption following OHCA causes poor neurological prognosis and the changes in the prognostic value of biomarkers. However, several tools to evaluate BBB disruption are either invasive or cannot provide a continuous monitoring. Blood retina barrier (BRB) is similar with BBB anatomically and functionally, and BRB disruption influences the pupillary light reflex (PLR). Therefore, we studied on the correlation between BBB permeability and NPi in OHCA patients treated with TTM.This study was prospectively conducted between October 2020 and March 2022 (**** IRB 2019-07-033-09). NPi and Albumin quotientt (Qa) to determine BBB permeability were presented every 2 h until 24 h, and then 48 h and 72 h after ROSC. 25 patients were required after sample size calculation, and partial correlation analysis between NPi and Qa was performed with prognostic control. Changes in NPi and Qa over time were analysed using the generalised estimating equation. Basal characteristics were in table 1 and figure 1. Since this study aimed to elucidate the correlation between NPi and Qa, data on NPi and Qa during seizures were included in this study. Additionally, the drug used in this study was found to have no effect on NPi in previous studies. NPi was lower, and Qa was higher in the group with poor neurological prognosis (Table 2,3, and Fig. 2). There was a moderate negative correlation between NPi and Qa (Fig. 3).This study demonstrated that NPi had a moderate negative correlation with BBB permeability in OHCA patients treated with TTM. Therefore, further studies on prognostic strategies using biomarkers and NPi considering the increase in BBB permeability are needed. 1
Abstract 15116: Left Ventricular Adaptation to Aortic Regurgitation in Adults With Repaired Coarctation of Aorta
Authors: Ahmed Goda, OMAR ABOZIED, Kartik Andi, Dhanya Ramachandran, Alexander C Egbe
Journal: Circulation (2022)

Background: Aortic regurgitation (AR) can develop in adults with repaired coarctation of aorta (COA), but there are limited data about left ventricular (LV) remodeling and clinical outcomes in this population. The purpose of the study was to compare LV remodeling (LV mass index [LVMI], LV ejection fraction [LVEF], and septal E/e’) and onset of symptoms before aortic valve replacement (AVR), and LV reverse remodeling (%-change in LVMI, LVEF and E/e’) after AVR in patients with versus without repaired COA presenting with AR. Methods:: Asymptomatic adults with repaired COA presenting with moderate/severe AR (AR-COA group) were matched 1:2 to asymptomatic adults without COA and similar severity of AR (control group). Results: Although both groups (AR-COA n=52, and control n=104) had similar age, sex, body mass index, aortic valve gradient, and AR severity, the AR-COA group had higher LVMI (124±28 versus 102±25 g/m2, p&lt;0.001) and E/e’ (12.3±2.3 versus 9.5±2.1, p=0.02) but similar LVEF (63±9% versus 67±10%, p=0.4). COA diagnosis (adjusted HR 1.95, 95%CI 1.49-2.37, p&lt;0.001), older age, E/e’, and LV hypertrophy wereassociated with onset of symptoms. Of 89 patients (AR-COA n=41, and control n=48) with echocardiographic data at 1-year post-AVR, the AR-COA group had less regression of LVMI (-8% [95%CI -5 to -11] versus -17% [95%CI -15 to -21], p&lt;0.001) and E/e’ (-5% [95% CI -3 to -7] versus -16% [95% CI -13 to -19], p&lt;0.001). Conclusions: Patients with COA and AR had a more aggressive clinical course, and perhaps may require a different threshold for surgical intervention.
Abstract 14936: Profiling of Microrna Expression in Extracellular Vesicles Released From Ischemic Skeletal Muscles in Hypercholesterolemic Conditions
Authors: Sylvie Dussault, Nozha Raguema, Yi Hui Luo, Michel Desjarlais, Alain Rivard
Journal: Circulation (2022)

Introduction: Hypercholesterolemia (HC) is an important cardiovascular risk factor associated with impaired neovascularization in response to ischemia. We found that specific microRNAs (miRs) whose levels are reduced in ischemic skeletal muscles of mice exposed to HC can rescue endothelial cell function and neovascularization. miRs can be transferred between cells via extracellular vesicles (EVs). EVs are involved in several biological functions including the response to ischemia and angiogenesis. Hypothesis: Here we tested the hypothesis that HC causes alterations in the miR content of EVs related to ischemia/neovascularization. Methods: We used a mouse model of peripheral artery disease to induce severe ischemia in the hindlimbs of hypercholesterolemic ApoE -/- and control C57Bl/6J mice. Microvesicles (MVs) and exosomes (exo) were isolated from ischemic skeletal muscles by differential centrifugation. Total RNA was extracted from these 2 types of EVs, and the miR content was analyzed using next generation sequencing. Results: Bioinformatic analysis of the 100 most expressed miRs in EVs showed an enrichment of 38 miRs in MVs compared to ischemic skeletal muscles, and an enrichment of 44 miRs in exo compared to ischemic skeletal muscles. Among enriched miRs, 27 are common to both MVs and exo. We identified specific miRs enriched in EVs that are known to modulate angiogenesis, including several miRs that were altered by HC. For example, among enriched miRs downregulated by HC in EVs, the let-7 family and miR-29a are known to be pro-angiogenic via inhibition of members of the TIMP family. On the other hand, among enriched miRs upregulated by HC in EVs, miR-199a and miR-16-5p are known to be anti-angiogenic via inhibition of VEGF. Conclusions: This study describes for the first time the effect of HC on the modulation of miR profile in EVs following skeletal muscle ischemia. We found that several angiogenesis-modulating miRs are enriched in EVs and altered by HC. Our findings constitute a solid framework for the identification of miRs that could be targeted to modify EV content in atherosclerotic conditions. Eventually these engineered EVs could serve as vectors to promote neovascularization and reduce ischemic damages in severe vascular diseases.